Surfactant proteins A and D bind to a variety of bacteria, viruses, allergens and apoptotic cells and thereby function as opsonins to enhance the uptake of these cells and particles. Binding of the collectins to pathogens occurs by various mechanisms. Some pathogens are aggregated by SP-A and/or SP-D and were phagocytized by immune cells like macrophages. SP-A and SP-D also have direct effects on immune cells and modulate the production of cytokines and inflammatory mediators.

The binding of SP-A and/or SP-D to the signal-inhibitory regulatory protein-α (SIRP-α) modulates cellular functions in a similar way like the binding complex of surfactant proteins with the CD91–calreticulin complex. In the absence of a pathogen, SP-A binds through its lectin domain to SIRP-α, whereas in the presence of a foreign organism or cell debris, to which the lectin domain of SP-A binds, the free collagen-like region activates immune cells through CD91–calreticulin. Importantly, engagement of the different receptors elicits different responses. Upon binding of SP-A to SIRP-α, the inflammatory-mediator production is inhibited. By contrast, SP-A enhances inflammatory mediator like tumour-necrosis factor (TNF), CXCL12 and CCL2 production through its binding to the CD91-calreticulin complex. Therefore, SP-A and SP-D both are able to enhance and inhibit inflammatory-mediator production to modulate the regulation of immune cells.

Another receptor that binds surfactant protein A was identified by Chroneos and colleagues and termed SP-R210 (Chroneos et al., 1996). Blocking of this receptor with specific antibodies leads to a loss of SP-A mediated functions, including inhibition of lymphocyte proliferation (Borron et al., 1998), enhanced uptake of bacteria by macrophages (Weikert et al., 1997) and mycobacterial killing by a nitric-oxide-dependent pathway (Weikert et al., 2000). Nevertheless, the molecular identity of SP-R210 is still unclear.

Numerous studies have reported that SP-A mediates cellular functions through C1q receptors37,38, including C1qR (also known as CD93)39,40 and calreticulin41,42. [...] However, recent studies have confirmed that calreticulin binds SP-A and SP-D and have shown that CD91 is a component of the
binding complex43. [...] Gardai and co-workers43 recently reported that SP-A and SP-D also modulate cellular functions through signal-inhibitory regulatory protein-α (SIRP-α), as well as the CD91-calreticulin complex. [...] For example, in the absence of a pathogen, SP-A binds through its lectin domain to SIRP-α. In the presence of a foreign organism or cell debris, to which the lectin domain of SP-A binds, the free collagen-like region activates immune cells through CD91–calreticulin. Importantly, engagement of the different receptors elicits different responses. When SP-A binds SIRP-α, inflammatory-mediator production is inhibited. By contrast, SP-A enhances inflammatory mediator (for example, tumour-necrosis factor (TNF),

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CXCL12 and CCL2) production through the CD91–calreticulin complex. This model provides at least a partial explanation for the apparently conflicting reports that SP-A and SP-D both enhance and inhibit inflammatory-mediator production and provides important information about mechanisms by which specific collectin responses might be mediated.

SP-R210 was identified more than eight years ago as an SP-A receptor45. SP-R210 was purified by SP-A affinity chromatography, and a SP-R210-specific antibody was shown to block SP-A-mediated functions, including inhibition of lymphocyte proliferation46, enhanced uptake of bacteria by macrophages47 and mycobacterial killing by a nitric-oxide-dependent pathway48. However, the molecular identity of SP-R210 has not yet been established.

[...]

Figure 3 Functions of SP-A and SP-D. Surfactant protein A (SP-A) and SP-D bind to a variety of bacteria, viruses, allergens and apoptotic cells and thereby function as opsonins to enhance the uptake of these cells and particles. Binding of the collectins to pathogens occurs by various mechanisms. Some pathogens are aggregated by SP-A and/or SP-D. SP-A and SP-D also have direct effects on immune cells and modulate the production of cytokines and inflammatory mediators.